A self-assembly heterotrinuclear gadolinium(III)-iron(II) complex as a MRI contrast agent

Article abstract of DOI:10.1016/j.inoche.2011.09.006

A new self-assembly gadolinium(III)-iron(II) complex (Gd₂Fe) was synthesized and characterized. Relaxivity studies showed that complex Gd ₂Fe exhibited higher relaxation efficiency compared with the clinically used Gd-DTPA. In vitro

Full text of DOI:10.1016/j.inoche.2011.09.006

Inorganic Chemistry Communications 14 (2011) 1898–1900
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Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
A self-assembly heterotrinuclear gadolinium(III)–iron(II) complex as a MRI
contrast agent
⁎
Wei-Sheng Li, Jian Luo, Zhong-Ning Chen
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2011
Accepted 7 September 2011
Available online 14 September 2011
A new self-assembly gadolinium(III)–iron(II) complex (Gd2Fe) was synthesized and characterized. Relaxivity
studies showed that complex Gd2Fe exhibited higher relaxation efficiency compared with the clinically used
Gd-DTPA. In vitro MR images on a 0.5 T magnetic field exhibited a remarkable enhancement of signal contrast
for Gd2Fe than Gd-DTPA. The results indicated that Gd2Fe could serve as a potential MRI contrast agent.
© 2011 Elsevier B.V. All rights reserved.
Keywords:
Gadolinium
Self-assembly
MRI
Relaxivity
Contrast agent
Magnetic resonance imaging (MRI) is one of the most useful diag-
nostic techniques in clinical medicine because it allows researchers
and doctors to image the body in a noninvasive manner [1,2]. Image
quality can be improved by the means of contrast agents which enhance
various portions of the MR image by changing, usually decreasing, the
relaxation time of the tissue water, thus allowing the area of interest
to be much more conspicuous than the surrounding tissues. Currently,
more than 35% of MRI examinations are performed by means of con-
trast agents [3].
Over the past decades, there have been many studies in the develop-
ment of new gadolinium based MR contrast agents. Particularly, much
effort has been focused on the development of targeted, high relaxivity,
and bioactivated contrast agents [4–19]. Recently, several self-assembly
heterobimetallic gadolinium(III)–iron(II/III) complexes as MRI contrast
agents with high relaxivity have been reported [20–25]. These supra-
molecular assemblies were prepared by linking multiple Gd3+-chelated
components with one Fen+ (n=2 or 3) ion to afford multicomponent
complexes with correspondingly longer rotational correlation times
and higher relaxivity values [26].
piperazine ethanesulfonic acid (HEPES, pH=7.2) buffer and human
serum albumin (HAS) solution. The potential application of Gd2Fe as
a new contrast agent was evaluated by in vitro T1-weighted phantom
images.
Synthetic routes to ligand H3L and complex Gd2Fe are shown in
Schemes 1 and 2, respectively. The syntheses of 1,4,7,10-tetraazacy-
clododecane-1,4,7-tetraacetate (Tris-tert-Bu-DO3A) (1) [29,30] and
4′-(4-bromomethyl-phenyl)-[2,2′;6′2″] terpyridine (tpy-ph-CH2Br)
(2) [31] have been previously reported. The synthesis was carried
out by the reaction of Tris-tert-Bu-DO3A (1) with tpy-ph-CH2Br (2)
in CH3CN and CH2Cl2 (v/v=1:1) in the presence of K2CO3 with stir-
ring at 40°C overnight to form 1-(4′-(4-methyl-phenyl)-[2,2′;6′2″]
terpyridine)-4,7,10-tris(tert-butoxycarbonyl-methyl)-1,4,7,10-tetraaza-
cyclododecane (tpy-ph-CH2-Tris-tert-Bu-DO3A) (3) in 62% yield. The
tpy-ph-CH2-Tris-tert-Bu-DO3A (3) was then deprotected in trifluoroace-
tic acid (TFA) and CH2Cl2 (v/v=1:1) to give tpy-ph-CH2-Tris-tert-DO3A
(H3L) in 85% yield. Complex Gd2Fe was synthesized in aqueous
solution by two-step procedures. The bis-complex Fe(H3L)2 was firstly
prepared by the reaction of Fe(NH4)2(SO4)2·6H2O with 2 equiv H3L.
Complexation of Fe(H3L)2 with Gd3+ was then performed by a portion
addition of GdCl3·6H2O to an aqueous solution of the Fe(H3L)2 by main-
taining pH at 7.1 using an aqueous ammonia solution. Upon stirring at
ambient temperature for 2 d, Gd2Fe complex was precipitated by addi-
tion of acetone and isolated as a deep violet power over dryness in
vacuo.
We have developed some tissue-targeted and Cu2+ responsive
MRI contrast agents with high T1 relaxivity in recent years [27–29].
In this report, we wish to describe designed synthesis and relaxivity
study of a new heterotrinuclear iron(II)–gadolinium(III)–iron(II)
complex (Gd2Fe). This Gd2Fe array was prepared by incorpation of
two Gd-containing units with an Fe2+ ion by self-assembly coordina-
tion. Subsequently, the T1 relaxivity was determined in hydroxyethyl
The T1-relaxivities of Gd2Fe complex in 50 mM HEPES buffer
(pH=7.2) and 0.725 mM HSA solutions are depicted in Fig. 1. The
T1-relaxivity of the Gd2Fe complex in 50 mM HEPES buffer (pH=
7.2) solution is 7.56 mM−1·s−1 with a correlation coefficient being
better than 0.99. For the purpose of comparison, the attempt to
⁎
Corresponding author.
E-mail address: czn@fjirsm.ac.cn (Z.-N. Chen).
1387-7003/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2011.09.006

W.-S. Li et al. / Inorganic Chemistry Communications 14 (2011) 1898–1900
1899
The increased relaxivities of the Gd2Fe complex relative to that of Gd-
DTPA arise likely from the rigidity of the low-spin Fe(tpy)2 unit which
also functions as an efficient spacer between the two Gd3+ ions to
avoid dipolar interactions that could accelerate electronic relaxation.
Consequently, the high relaxivity of complex Gd2Fe complex is attributed
to both the rigidity of the whole complex ensured by the rationally
designed molecular framework and the relatively long Gd−Gd distance
which excludes dipole–dipole interactions between the paramagnetic
centers [23].
Serum albumin is the richest protein of mammal blood plasma and
plays a crucial role in the uptake, transportation, biodistribution, and ex-
cretion of the contrast agent in human body [32]. The relaxation times
(T1) for various concentrations of the Gd2Fe complex (0–1.8 mM) in
0.725 mM HSA solution were measured. The relaxivity was also obtained
from the linear regression according to Eq. S1 (Supporting information).
Fig. 1 illustrates a reasonable enhancement of solvent proton relaxation
rates for the Gd2Fe complex in HSA solution. It is 8.66 mM−1·s−1 with
a correlation coefficient better than 0.99, which is 1.15 times of that for
the Gd2Fe complex in 50 mM HEPES buffer (pH=7.2). It is most likely
that other paramagnetic species exist in HSA solution besides free
Gd2Fe complex. Since the equilibrium constant for the binding of Gd3+
to the serum albumin is very small relative to the stability constant of
Gd2Fe complex [33], the possible release of Gd3+ from Gd2Fe complex
could be ignored. The enhancement is attributable to Gd2Fe complex
which is likely non-covalently bound to HSA.
N
N
N
a
COOBut
COOBut
N
N
N
N
NH
N
+
N
Br
ButOOC
b
N
COOBut
N
N
N
N
N
N
COOBut
COOH
ButOOC
c
N
N
N
N
MR images of Gd2Fe and Gd-DTPA complexes were obtained in glass
capillaries (1 mm) at 0.5 T (Fig. 2). The concentrations of the Gd2Fe
complex are ranged from 100 μM to 1 μM and that of Gd-DTPA was
100 μM. The images were obtained using an NMI20-Analyst NMR Ana-
lyzing and Imaging system with a TE and TR of 60 and 4000 ms, number
of acquisitions=1. As shown in Fig. 2, the intensity was distinctly
brighter in comparison with the one taken in the absence of any con-
trast agent. There was sufficient enhancement of the contrast in the im-
ages at concentration above 10 μM. Obviously, the image of 100 μM
Gd2Fe complex is much brighter than that of 100 μM Gd-DTPA complex.
In summary, a new gadolinium(III)–iron (II) complex with high T1-
relaxivity was synthesized and characterized, which is a potential MRI
contrast agent due to its facile synthetic procedures. The Gd2Fe complex
has a well-defined topology with favorable features to attain high relax-
ivities. It has a rigid Fe2+(tpy-ph-CH2) core and an efficient separation of
the two Gd3+ centers.
N
N
N
COOH
HOOC
H3L
Scheme 1. Synthetic routes to ligand H3L. (a) N-bromosuccinimide (NBS). azodiisobutyro-
nitrile(AIBN). CCl4, 80 °C; (b) K2CO3, CH2Cl2 and CH3CN, 40 °C; (c) F3CCOOH, CH2Cl2, rt.
measure the relaxivity of complex GdL was unsuccessful due to its poor
solubility, which is similar to tpy-DTTA4− [23]. The relaxivity of Gd2Fe
complex (7.56 mM−1·s−1) in 50 mM HEPES buffer (pH=7.2) is higher
than that of commercial contrast agent Gd-DTPA (5.29 mM−1·s−1) [27].
N
COOH
COOH
N
N
N
N
N
Acknowledgments
N
This work was supported by the NSFC (21001106), the 973 pro-
ject (2007CB815304) from MSTC, and the NSF of Fujian Province
(2009J05039).
HOOC
Fe2+
COOH
HOOC
HOOC
N
N
N
N
2+
N
N
N
N
N
14
HSA
COOH
Fe
N
12
HEPES buffer
N
N
N
N
10
8
COOH
HOOC
Gd3+
O
C
O
6
C
O
N
N
N
4
2+
O
Gd
N
N
O
N
N
N
O
N
2
C
N
Fe
C
N
Gd
N
N
O
O
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Gd3+/mM
O
O
C
N
C
Fig. 1. The relaxation rates of water proton vs the concentrations of Gd2Fe complex in
50 mM HEPES buffer (pH=7.2) and 0.725 mM HSA solutions. The T1-relaxivities,
calculated from the slopes of the fitting curves, are 7.56 mM·s−1 in 50 mM HEPES buffer
and 8.66 mM·s−1 in 0.725 mM HSA solutions.
O
O
Scheme 2. Synthetic routes to Gd2Fe complex.

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